TY - JOUR
T1 - A pulse rapamycin therapy for infantile spasms and associated cognitive decline
AU - Raffo, Emmanuel
AU - Coppola, Antonietta
AU - Ono, Tomonori
AU - Briggs, Stephen W.
AU - Galanopoulou, Aristea S.
N1 - Funding Information:
This work was supported by NINDS/NICHD grant NS62947 , NINDS research grants NS20253 , NS58303 , NS45243 , as well as grants from People Against Childhood Epilepsy , the International Rett Syndrome Foundation , and the Heffer Family Foundation . We would like to thank Dr Solomon Moshé for thoughtful comments and discussions as well as acknowledge the outstanding technical assistance of our technicians, Mrs Qianyun Li, Mrs Wei Liu, and Mrs Hong Wang. S.W.B is a graduate student at the MSTP of the Albert Einstein College of Medicine.
PY - 2011/8
Y1 - 2011/8
N2 - Infantile spasms are seizures manifesting within a spectrum of epileptic encephalopathies of infancy that often lead to cognitive impairment. Their current therapies, including adrenocorticotropic hormone (ACTH), high dose steroids, or vigabatrin, are not always effective and may be associated with serious side effects. Overactivation of the TORC1 complex of the mTOR pathway is implicated in the pathogenesis of certain genetic and acquired disorders that are linked with infantile spasms, like tuberous sclerosis. Here, we tested the therapeutic potential of rapamycin, a TORC1 inhibitor, as a potential treatment for infantile spasms in the multiple-hit rat model of ACTH-refractory symptomatic infantile spasms, which is not linked to tuberous sclerosis. Rapamycin or vehicle was given after spasms appeared. Their effects on spasms, other seizures, performance in Barnes maze, and expression of the phosphorylated S6 ribosomal protein (pS6: a TORC1 target) in the cortex, using immunofluorescence, were compared. Rapamycin suppressed spasms dose-dependently and improved visuospatial learning, although it did not reduce the frequency of other emerging seizures. High-dose pulse rapamycin effected acute and sustained suppression of spasms and improved cognitive outcome, without significant side effects. Therapeutically effective rapamycin doses normalized the pS6 expression, which was increased in perilesional cortical regions of pups with spasms. These findings support that pathological overactivation of TORC1 may be implicated in the pathogenesis of infantile spasms, including those that are not linked to tuberous sclerosis. Furthermore, a high-dose, pulse rapamycin treatment is a promising, well tolerated and disease-modifying new therapy for infantile spasms, including those refractory to ACTH.
AB - Infantile spasms are seizures manifesting within a spectrum of epileptic encephalopathies of infancy that often lead to cognitive impairment. Their current therapies, including adrenocorticotropic hormone (ACTH), high dose steroids, or vigabatrin, are not always effective and may be associated with serious side effects. Overactivation of the TORC1 complex of the mTOR pathway is implicated in the pathogenesis of certain genetic and acquired disorders that are linked with infantile spasms, like tuberous sclerosis. Here, we tested the therapeutic potential of rapamycin, a TORC1 inhibitor, as a potential treatment for infantile spasms in the multiple-hit rat model of ACTH-refractory symptomatic infantile spasms, which is not linked to tuberous sclerosis. Rapamycin or vehicle was given after spasms appeared. Their effects on spasms, other seizures, performance in Barnes maze, and expression of the phosphorylated S6 ribosomal protein (pS6: a TORC1 target) in the cortex, using immunofluorescence, were compared. Rapamycin suppressed spasms dose-dependently and improved visuospatial learning, although it did not reduce the frequency of other emerging seizures. High-dose pulse rapamycin effected acute and sustained suppression of spasms and improved cognitive outcome, without significant side effects. Therapeutically effective rapamycin doses normalized the pS6 expression, which was increased in perilesional cortical regions of pups with spasms. These findings support that pathological overactivation of TORC1 may be implicated in the pathogenesis of infantile spasms, including those that are not linked to tuberous sclerosis. Furthermore, a high-dose, pulse rapamycin treatment is a promising, well tolerated and disease-modifying new therapy for infantile spasms, including those refractory to ACTH.
KW - Barnes maze
KW - Cerebral cortex
KW - Infantile spasms
KW - Learning
KW - MTOR
KW - Rapamycin
KW - Rat
KW - Ribosomal S6 protein
KW - Seizure
KW - Seizures
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U2 - 10.1016/j.nbd.2011.03.021
DO - 10.1016/j.nbd.2011.03.021
M3 - Article
C2 - 21504792
AN - SCOPUS:79958184395
SN - 0969-9961
VL - 43
SP - 322
EP - 329
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 2
ER -